Use of oxoquinazoline derivatives in the treatment of hyperuricaemia

ABSTRACT

Oxoquinazoline derivatives of formulae ##STR1## (the symbols are defined in the specification) are well-tolerated drugs for treating hyperuricaemia.

The invention relates to the use of certain known oxoquinazolinederivatives in the treatment of hyperuricaemia.

Hyperuricaemia is the pathophysiological cause of gout. The drugscurrently available for the treatment of hyperuricaemia are admittedlyeffective but have various undesirable effects. They are eitheruricosurics (agents which increase the secretion of uric acid, such asprobenecid, sulphine pyrazone, benz bromarone) or uricostatics (agentswhich inhibit the synthesis of uric acid, such as allopurinol).

The profile of side effects of these preparations is specifically asfollows:

with probenecid, 10% of patients may suffer gastro-intestinal disordersand in 4% of cases there may be allergic skin reactions and in someindividual instances nephrotic syndrome (kidney disease) has also beendescribed.

Sulphine pyrazone simultaneously acts as a thrombocyte aggregationinhibitor and may also lead to gastro-intestinal disorders. In addition,sodium retention (leading to water retention) and in individual casesagranulocytosis (damage to the blood-forming system) are also described.

The administration of benzbromarone may also lead to gastro-intestinaldisorders.

Apart from gastro-intestinal disorders, allopurinol may also result inundesirable effects on the blood-forming system, although these areextremely rare. Pruritus and allergies occur relatively frequently andin rare cases Lyell syndrome (scalded skin syndrome) is also described.

It has now been found that, surprisingly, the compounds according toGerman Offenlegungsschrift P 25 57 425 (or French Application No. 76 38135) and European Patent Application 0 113 911 are particularly suitablefor the treatment of hyperuricaemia.

The substances which may be used according to the invention arecompounds of formula ##STR2## wherein A represents one of the groups--CH═CH--, --CH═N-- or S,

R₁ represent

(a) hydrogen, a lower alkyl or alkoxy group or a condensed-on benzenering or

(b) a cyano, tetrazol-5-yl or -COR₃ group,

R₂ represents a cyano, tetrazol-5-yl or --COR₄ group or, if R₁ has oneof the meanings given in (b), R₂ may also represent hydrogen, a loweralkyl or alkoxy group or a condensed on benzene ring,

R₃ represents a lower alkoxy group, an amino, hydroxylamino ortetrazol-5-yl amino group or, if R₂ does not represent hydrogen, R₃ mayalso represent a hydroxy group and

R₄ represents a lower alkoxy group, a hydroxy, amino, hydroxylamino ortetrazol-5-ylamino group,

which may occur as free compounds or as salts with or possibly bases,and compounds of formula ##STR3## wherein either R₅ and R₆ representhydrogen, lower alkyl, lower alkoxy or a condensed--on benzene ring andR₇ and R₈ together represent the group --N═N--NH-- or R₅ and R₆ togetherrepresent the group --N═N--NH-- and R₇ and R₈ represent hydrogen, loweralkyl, lower alkoxy or a condensed--on benzene ring, and the salts ofthese compounds with basic substances.

Compounds from German Offenlegungsschrift P 25 57 425 which areparticularly worth considering for the indication according to theinvention are characterized, for example, by the following formula:##STR4## whilst the groups R and R' have the following pairs definitions(R being mentioned first in each case):

    ______________________________________                                        H/COOH             COOH/H                                                     CH.sub.3 /COOH     COOH/CH.sub.3                                              OCH.sub.3 /COOH    COOH/OCH.sub.3                                             CH(CH.sub.3).sub.2 /COOH                                                                         COOH/CH(CH.sub.3).sub.2                                    H/tetrazol-5-yl    tetrazol-5-yl/H                                            H/CONH.sub.2                                                                  H/CN                                                                          ______________________________________                                    

compounds from the above-mentioned European application which areparticularly useful according to the invention are the compounds of thefollowing formulae: ##STR5## wherein R" represents H, CH₃, C₂ H₅,CH(CH₃)₂ or OCH₃ and ##STR6## wherein R" is defined as hereinbefore.

The above-mentioned compounds have already been described aspharmaceutical compositions. The fields of application given were: theprevention and treatment of allergic diseases such as asthma, hayfever,conjunctivitis, urticaria, eczema and dermatitis. Their muscle-relaxant(bronchodilatory) and vasodilatory activity have also been mentioned.

There is no reference to any uric acid-reducing activity, nor is such aneffect made obvious by the known effects.

Compared with the known agents for treating hyperuricaemia or gout, thecompounds which may be used according to the invention, for example11-oxo-11-H-pyrido[2,1-b]-quinazolin-2-carboxylic acid and the saltsthereof, have the advantage of being better tolerated. Thus, when morethan 1000 patients were treated with this compound for a different typeof indication, no side effects specific to the preparation werediscovered.

For use, the compounds are processed in the usual way to formconventional galenic preparations. The primary form of administration isby oral route, preferably in capsule form; however, all other oral formsmay be considered, e.g. tablets, coated tablets, granules, suspensionsor delayed release forms.

The daily dosage is about 100 to 1000 mg; it may be given in 1-3 singledoses.

In a study carried out on 12 ambulant patients with symptom-freehyperuricaemia, the patients were treated with11-oxo-11-H-pyrido[2,1-b]quinazolin-2-carboxylic acid in the form oftablets containing the usual excipients. The dosage was 200 mg 3 times aday for 2 weeks with a subsequent wash-out phase lasting 1 week. Beforethe treatment the uric acid levels in the serum were on average 8.56±0.6mg/100 ml. After two weeks' treatment these fell significantly by 29% to6.1±0.8 mg/100 ml. After the washout phase they to 7.7 mg ±0.9 mg/100ml.

In another study, 8 stationary test subjects were fed with a purine-richdiet for 8 days continuously. This produced a higher level of uric acidin the serum, which was stable from the third day onwards. From the 5thday onwards the test subjects were additionally given 3×200 mg per dayof the abovementioned compound in tablet form. On the 4th day on thediet the uric acid levels had stabilized at 7.9±0.95 mg/100 ml at araised level. After the end of treatment (4 days), i.e. at the end ofthe 8th day of the trial, the levels had fallen significantly by 35% to5.1±0.82 mg/100 ml. Once again, the compound was found a significantlowering effect on uric acid.

EXAMPLES OF FORMULATIONS

1. Tablets

    ______________________________________                                        11-Oxo-11-H--pyrido[2,1-b]-                                                   quinazolin-2-carboxylic acid                                                                          100    g                                              Colloidal silica        10     g                                              Lactose                 118    g                                              Potato starch           60     g                                              Polyvinylpyrrolidone    6      g                                              Sodium cellulose glycolate                                                                            4      g                                              Magnesium stearate      2      g                                              ______________________________________                                    

The ingredients are processed in the usual way to form tablets weighing300 mg.

2. Capsules

    ______________________________________                                        Active substance of formula I or II                                                                  300 g                                                  Corn starch            100 g                                                  ______________________________________                                    

The ingredients are thoroughly mixed and the mixture

transferred in batches of 400 mg into oblong gelatin capsules.

What is claimed is:
 1. A method for treating hyperuricaemisa or adisease state caused thereby, which method comprises orallyadministering, to a host suffering from hyperuricaemia or a diseasestate caused thereby, a therapeutic amount of a compound of the formula##STR7## wherein R and R¹ are respectively: H and COOH, CH₃, and COOH,OCH₃ and COOH, CH(CH₃)₂ and COOH, H and tetrazol-5-yl, H and CONH₂, Hand CN, COOH and H, COOH and CH₃, COOH and OCH₃, COOH and CH(CH₃)₂, ortetrazol-5-yl and H.
 2. A method for treating hyperuricaemia or adisease state caused thereby, which method comprises orallyadministering, to a host suffering from hyperuricaemia or a diseasestate caused thereby, a therapeutic amount of a compound of the formula##STR8## wherein R" represents H, CH₃, C₂ H₅, CH(CH₃)₂ or OCH₃ or of theformula ##STR9## wherein R" has the meanings given hereinbefore.
 3. Amethod for treating hyperuricaemia or a disease state caused thereby,which method comprises orally administering, to a host suffering fromhyperuricaemia or a disease state caused thereby, a therapeutic amountor 11-oxo-11-H-pyrido[2,1-b]quinazolin-2- carboxylic acid or apharmaceutically acceptable salt thereof.
 4. A method for treatinghyperuricaemia or a disease state caused thereby, which method comprisesorally administering, to a host suffering from hyperuricaemia or adisease state caused thereby, a therapeutic amount of a compound of theformula ##STR10## wherein, A represents a sulfur atomR₁ represents (a)hydrogen, a lower alkyl or alkoxy group or a condensed-on benzene ringor (b) a cyano, tetrazol-5-yl or --COR₃ group, represents a cyano,tetrazol-5-yl or --COR₄ group or if R₁ has one of the meanings given in(b), R₂ may also represent hydrogen, a lower alkyl or alkoxy group or acondensed-on benzene ring, R₃ represents a lower alkoxy group, an amino,hydroxylamino or tetrazol-5-yl amino group or, if R2 does not representhydrogen, R₃ may also represent a hydroxy group and R₄ represents alower alkoxy group, a hydroxy, amino, hydroxylamino or tetrazol-5-ylamino group, or a pharmaceutically acceptable salt thereof.
 5. A methodfor treating hyperuricaemia or a disease state caused thereby, whichmethod comprises orally administering, to a host suffering fromhyperuricaemia or a disease state caused thereby, a thereapeutic amountof a compound of the formula ##STR11## wherein either R₅ and R₆represent hydrogen, lower alkyl, lower alkoxy or a condensed--on benzenering and R₇ and R₈ together represent the group --N═N--NH-- or R₅ and R₆together represent the group --N═N--NH-- and R₇ and R₈ representhydrogen, lower alkyl, lower alkoxy or a condensed--on a benzene ring,or a pharmaceutically acceptable salt thereof.